Often a diagnosis of exclusion, skin biopsy shows a neutrophillic inflammatory infiltrate.

Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of Anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA.

If the person has kidney failure or cutaneous vasculitis, a biopsy is obtained from the kidneys. On rare occasions, thoracoscopic lung biopsy is required. On histopathological examination, a biopsy will show "leukocytoclastic vasculitis" with necrotic changes and granulomatous inflammation (clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the name granulomatosis with polyangiitis, although it is not an essential feature. Nevertheless, necrotizing granulomas are a hallmark of this disease. However, many biopsies can be nonspecific and 50% provide too little information for the diagnosis of GPA.

In 1990, the American College of Rheumatology accepted classification criteria for GPA. These criteria were not intended for diagnosis, but for inclusion in randomized controlled trials. Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing GPA.

- Nasal or oral inflammation:

- painful or painless oral ulcers "or"

- purulent or bloody nasal discharge

- Lungs: abnormal chest X-ray with:

- nodules,

- infiltrates "or"

- cavities

- Kidneys: urinary sediment with:

- microhematuria "or"

- red cell casts

- Biopsy: granulomatous inflammation

- within the arterial wall "or"

- in the perivascular area

According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands:

- a granulomatous inflammation involving the respiratory tract, and

- a vasculitis of small to medium-size vessels.

Several investigators have compared the ACR and Chapel Hill criteria.

A detailed history is important to elicit any recent medications, any risk of hepatitis infection, or any recent diagnosis with a connective tissue disorder such as systemic lupus erythematosus (SLE). A thorough physical exam is needed as usual.

- Lab tests. Basic lab tests may include a CBC, chem-7 (look for creatinine), muscle enzyme, liver function tests, ESR, hepatitis seroloties, urinalysis, CXR, and EKG. Additional, more specific tests include:

- Antinuclear antibody (ANA) test can detect an underlying connective tissue disorder, especially SLE

- Complement levels that are low can suggest mixed cryoglobulinemia, hepatitis C infection, and SLE, but not most other vasculitides.

- Antineutrophil cytoplasmic antibody (ANCA) may highly suggest granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, or drug-induced vasculitis, but is not diagnostic.

- Electromyography. It is useful if a systemic vasculitis is suspected and neuromuscular symptoms are present.

- Arteriography. Arteriograms are helpful in vasculitis affecting the large and medium vessels but not helpful in small vessel vasculitis. Angiograms of mesenteri or renal arteries in polyarteritis nodosa may show aneurysms, occlusions, and vascular wall abnormalities. Arteriography are not diagnostic in itself if other accessible areas for biopsy are present. However, in Takayasu's arteritis, where the aorta may be involved, it is unlikely a biopsy will be successful and angiography can be diagnostic.

- Tissue biopsy. This is the gold standard of diagnosis when biopsy is taken from the most involved area.

Diagnostic markers include eosinophil granulocytes and granulomas in affected tissue, and antineutrophil cytoplasmic antibodies (ANCA) against neutrophil granulocytes. The American College of Rheumatology 1990 criteria for diagnosis of Churg–Strauss syndrome lists these criteria:

- Asthma

- Eosinophilia, i.e. eosinophil blood count greater than 500/microliter, or hypereosinophilia, i.e. eosinophil blood count greater than 1,500/microliter

- Presence of mononeuropathy or polyneuropathy

- Unfixed pulmonary infiltrates

- Presence of paranasal sinus abnormalities

- Histological evidence of extravascular eosinophils

For classification purposes, a patient shall be said to have Churg–Strauss syndrome (CSS) if at least four of these six criteria are positive. The presence of any four or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7%.

The French Vasculitis Study Group has developed a five-point system ("five-factor score") that predicts the risk of death in Churg–Strauss syndrome using clinical presentations. These factors are:

- Reduced renal function (creatinine >1.58 mg/dl or 140 µmol/l)

- Proteinuria (>1 g/24h)

- Gastrointestinal hemorrhage, infarction, or pancreatitis

- Involvement of the central nervous system

- Cardiomyopathy

The lack of any of these factors indicates milder case, with a five-year mortality rate of 11.9%. The presence of one factor indicates severe disease, with a five-year mortality rate of 26%, and two or more indicate very severe disease: 46% five-year mortality rate.

Aspiration pneumonia is typically caused by aspiration of bacteria from the oral cavity into the lungs, and does not result in the formation of granulomas. However, granulomas may form when food particles or other particulate substances like pill fragments are aspirated into the lungs. Patients typically aspirate food because they have esophageal, gastric or neurologic problems. Intake of drugs that depress neurologic function may also lead to aspiration. The resultant granulomas are typically found around the airways (bronchioles) and are often accompanied by foreign-body-type multinucleated giant cells, acute inflammation or organizing pneumonia. The finding of food particles in lung biopsies is diagnostic.

The diagnosis is usually made by tissue biopsy, however this cannot reliably distinguish between the granulomas of OFG and those of Crohn's disease or sarcoidosis. Other causes of granulomatous inflammation are ruled out, such as sarcoidosis,

Crohn's disease, allergic or foreign body reactions and mycobacterial infections.

A foreign-body granuloma occurs when a foreign body (such as a wood splinter, piece of metal, glass etc.) penetrates the body's soft tissue followed by acute inflammation and formation of a granuloma. In some cases the foreign body can be found and removed even years after the precipitating event.

The differential diagnosis of Rosai–Dorfman disease includes both malignant and nonmalignant diseases, such as granulomatosis with polyangiitis, Langerhans cell histiocytosis, Langerhans cell sarcoma, lymphoma, sarcoidosis, and tuberculosis. The disease is diagnosed by biopsy of affected tissues. Microscopic examination of stained specimens will show histiocytes with lymphocytes and possibly other types of cells trapped within them, a phenomenon known as emperipolesis. Upon immunohistochemical staining, the histiocytes will be positive for S100, CD68, and CD163 but negative for CD1a.

First-line therapy for disseminated or localized instances of pyoderma gangrenosum is systemic treatment by corticosteroids and ciclosporin. Topical application of clobetasol, mupirocin, and gentamicin alternated with tacrolimus can be effective.

Pyoderma gangrenosum ulcers demonstrate pathergy, that is, a worsening in response to minor trauma or surgical debridement. Significant care should be taken with dressing changes to prevent potentially rapid wound growth. Many patients respond differently to different types of treatment, for example some benefit from a moist environment, so treatment should be carefully evaluated at each stage.

Papules that begin as small "spouts" can be treated with Dakins Solution to prevent infection and wound clusters also benefit from this disinfectant. Wet to dry applications of Dakins can defeat spread of interior infection. Heavy drainage can be offset with Coban dressings. Grafting is not recommended due to tissue necrosis.

If ineffective, alternative therapeutic procedures include systemic treatment with corticosteroids and mycophenolate mofetil; mycophenolate mofetil and ciclosporin; tacrolimus; thalidomide; infliximab; or plasmapheresis.

There is currently a phase III trial for the use of the IL-1B modulating agent gevokizumab in treating the ulcers of pyoderma gangrenosum.

In this table: ANA = Antinuclear antibodies, CRP = C-reactive protein, ESR = Erythrocyte Sedimentation Rate, "ds"DNA = double-stranded DNA, ENA = extractable nuclear antigens, RNP = ribonucleoproteins; VDRL = Venereal Disease Research Laboratory

Treatment protocol is not well established. Some sources report that approximately half of the patients will fully recover after lengthy (mean time 14.5 months, range 2–24 months) expectant management.

Treatment with steroids is lengthy and usually requires about 6 months. While some source report very good success with steroids most report a considerable risk of recurrence after a treatment with steroids alone. Steroids are known to cause elevation of prolactin levels and increase risk of several conditions such as diabetes, and other endocrinopathies which in turn increase the risk of IGM. Treatment with topical steroids to limit side effects was also reported in one case. For surgical treatment recurrence rates of 5-50% have been reported.

A 1997 literature review article recommended complete resection or corticosteroid therapy, stating also that long-term follow-up was indicated due to a high rate of recurrence.

Treatment with a combination of glucocorticoids and prolactin lowering medications such as bromocriptine or cabergoline was used with good success in Germany. Prolactin lowering medication has also been reported to reduce the risk of recurrence. In cases of drug-induced hyperprolactinemia (such as antipsychotics) prolactin-sparing medication can be tried.

Methotrexate alone or in combination with steroids has been used with good success. Its principal mechanism of action is immunomodulating activity, with a side effect profile that is more favorable for treating IGM.

Colchicine, azathioprine and NSAIDs have also been used.

Anti-tumour necrosis factor α antagonists (e.g. infliximab)

Dietary restriction of a particular suspected or proven antigen may be involved in the management of OFG, such as cinnamon or benzoate-free diets.

Treatment is targeted to the underlying cause. However, most vasculitis in general are treated with steroids (e.g. methylprednisolone) because the underlying cause of the vasculitis is due to hyperactive immunological damage. Immunosuppressants such as cyclophosphamide and azathioprine may also be given.

A systematic review of antineutrophil cytoplasmic antibody (ANCA) positive vasculitis identified best treatments depending on whether the goal is to induce remission or maintenance and depending on severity of the vasculitis.

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease.

A physical examination will demonstrate many of the features listed above.

Blood tests

- Complete blood count may reveal normocytic anemia and eventually thrombocytosis.

- Erythrocyte sedimentation rate will be elevated.

- C-reactive protein will be elevated.

- Liver function tests may show evidence of hepatic inflammation and low serum albumin levels.

Other optional tests include:

- Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis.

- Echocardiogram may show subtle coronary artery changes or, later, true aneurysms.

- Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder.

- Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth.

- Lumbar puncture may show evidence of aseptic meningitis.

- Angiography was historically used to detect coronary artery aneurysms, and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.

- Temporal artery biopsy

Some patients have no symptoms, spontaneous remission, or a relapsing/remitting course, making it difficult to decide whether therapy is needed. In 2002, authors from Sapienza University of Rome stated on the basis of a comprehensive literature review that "clinical observation without treatment is advisable when possible."

Therapeutic options include surgery, radiation therapy, and chemotherapy. Surgery is used to remove single lymph nodes, central nervous system lesions, or localized cutaneous disease. In 2014, Dalia and colleagues wrote that for patients with extensive or systemic Rosai–Dorfman disease, "a standard of care has not been established" concerning radiotherapy and chemotherapy.

Diagnosis is sometimes difficult because the early phases of the disease often resemble eczema or even psoriasis. As with any serious disease,

it is advisable to pursue the opinion of a medical professional if a case is suspected. Diagnosis is generally accomplished through a skin biopsy. Several biopsies are recommended, to be more certain of the diagnosis. The diagnosis is made through a combination of the clinical picture and examination, and is confirmed by biopsy.

To stage the disease, various tests may be ordered, to assess nodes, blood and internal organs, but most patients present with disease apparently confined to the skin, as patches (flat spots) and plaques (slightly raised or 'wrinkled' spots).

Peripheral smear will often show buttock cells.

Inflammation, or vasculitis of the arteries and veins occurs throughout the body. This is usually caused by increased production of the cells of the immune system to a pathogen, or autoimmunity. Systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls. Under this classification scheme for systemic vasculitis, Kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angiitis), which may be identified histologically by the occurrence of necrosis (tissue death), fibrosis, and proliferation of cells associated with inflammation in the inner layer of the vascular wall.

Other diseases featuring necrotizing vasculitis include polyarteritis nodosa, granulomatosis with polyangiitis (GPA), Henoch–Schönlein purpura and eosinophilic granulomatosis with polyangiitis (EGPA).

Kawasaki disease may be further classified as a medium-sized-vessel vasculitis, affecting medium- and small-sized blood vessels, such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100 µm in diameter. Kawasaki disease is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18. A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to distinguish them and suggest a more concrete set of diagnostic criteria for each. Within this classification of childhood vasculitides, Kawasaki disease is, again, a predominantly medium-sized vessel vasculitis.

It is also an autoimmune form of vasculitis, and is not associated with ANCA antibodies, unlike other vasculitic disorders associated with them (such as granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis). This categorization is considered essential for appropriate treatment.

Pauci-immune (pauci- Latin: few, little) vasculitis is a form of vasculitis that is associated with minimal evidence of hypersensitivity upon immunofluorescent staining for IgG.

Normally a kidney sample will be subjected to immunofluorescence if rapidly progressive glomerulonephritis is a concern. In this case, the immunofluorescence can show three patterns: linear, granular and negative (pauci-immune). The linear and granular patterns are examples of positive immunofluorescence and are associated with Goodpasture syndrome and post-streptococcal glomerulonephritis accordingly. A negative pattern or pauci-immune pattern can be associated with systemic vasculitis such as microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (EGPA) or granulomatosis with polyangiitis (GPA). In many cases however, it is limited to the kidney and it is thus called idiopathic.

Since it can be associated with the three systemic vasculitides mentioned above, a pauci-immune pattern finding can be associated with antineutrophil cytoplasmic antibodies (ANCA). Therefore, an ANCA test should follow a negative immunofluorescence result in order to distinguish between the above-mentioned systemic vasculitis.

Peak incidences in 50- to 60-year-olds symptoms include intermittent fever / weight loss / shortness of breath / joint pain.

Idiopathic granulomatous mastitis is defined as granulomatous mastits without any other attributable cause such as those above mentioned. It occurs on average two years and almost exclusively up to six years after pregnancy, usual age range is 17 to 42 years. Some cases have been reported that were related to drug induced hyperprolactinemia.

Exceptionally rarely it has been diagnosed during pregnancy and in men.

Traditionally, mycosis fungoides has been divided into three stages: premycotic, mycotic and tumorous. The premycotic stage clinically presents as an erythematous (red), itchy, scaly lesion. Microscopic appearance is non-diagnostic and represented by chronic nonspecific dermatosis associated with psoriasiform changes in epidermis.

In the mycotic stage, infiltrative plaques appear and biopsy shows a polymorphous inflammatory infiltrate in the dermis that contains small numbers of frankly atypical lymphoid cells. These cells may line up individually along the epidermal basal layer. The latter finding if unaccompanied by spongiosis is highly suggestive of mycosis fungoides. In the tumorous stage a dense infiltrate of medium-sized lymphocytes with cerebroid nuclei expands the dermis.

Otomycosis is treated by debridment followed with topical azole antifungals, and symptomatically managed with oral antihistamines. Per a study in Iran 10cc acetic acid 2% plus 90 cc of isopropyl alcohol 70% was effective.

The best imaging modality for idiopathic orbital inflammatory disease is contrast-enhanced thin section magnetic resonance with fat suppression. The best diagnostic clue is a poorly marginated, mass-like enhancing soft tissue involving any area of the orbit.

Overall, radiographic features for idiopathic orbital inflammatory syndrome vary widely. They include inflammation of the extraocular muscles (myositis) with tendinous involvement, orbital fat stranding, lacrimal gland inflammation and enlargement (dacryoadenitis), involvement of the optic sheath complex, uvea, and sclera, a focal intraorbital mass or even diffuse orbital involvement. Bone destruction and intracranial extension is rare, but has been reported. Depending on the area of involvement, IOI may be categorized as:

- Myositic

- Lacrimal

- Anterior – Involvement of the globe, retrobulbar orbit

- Diffuse – Multifocal intraconal involvement with or without an extraconal component

- Apical – Involving the orbital apex and with intracranial involvement

Tolosa–Hunt syndrome is a variant of orbital pseudotumor in which there is extension into the cavernous sinus through the superior orbital fissure. Another disease variant is Sclerosing pseudotumor, which more often presents bilaterally and may extend into the sinuses.

CT findings

In non-enhanced CT one may observe a lacrimal, extra-ocular muscle, or other orbital mass. It may be focal or infiltrative and will have poorly circumscribed soft tissue. In contrast-enhanced CT there is moderate diffuse irregularity and enhancement of the involved structures. A dynamic CT will show an attenuation increase in the late phase, contrary to lymphoma where there is an attenuation decrease. Bone CT will rarely show bone remodeling or erosion, as mentioned above.

MR findings

On MR examination there is hypointensity in T1 weighted imaging (WI), particularly in sclerosing disease. T1WI with contrast will show moderate to marked diffuse irregularity and enhancement of involved structures. T2 weighted imaging with fat suppression will show iso- or slight hyperintensity compared to muscle. There is also decreased signal intensity compared to most orbital lesions due to cellular infiltrate and fibrosis. In chronic disease or sclerosing variant, T2WI with FS will show hypointensity (due to fibrosis). Findings on STIR (Short T1 Inversion Recovery) are similar to those on T2WI FS. In Tolosa–Hunt syndrome, findings include enhancement and fullness of the anterior cavernous sinus and superior orbital fissure in T1WI with contrast, while MRA may show narrowing of cavernous sinus internal carotid artery (ICA).

Ultrasonographic findings

On grayscale ultrasound there is reduced reflectivity, regular internal echoes, and weak attenuation, in a way, similar to lymphoproliferative lesions.